The present invention provides a genus of optionally substituted Schiff base condensation products (and the carba analogs thereof) comprising an amino acid component and a benzaldehyde component, that have MIF (macrophage migration inhibitory factor) antagonist activity. Specifically, the compounds are useful for treating a variety of diseases involving inflammatory activity or pro-inflammatory cytokine responses, such as autoimmune diseases, asthma, arthritis, EAE, ARDS and various forms of sepsis and septic shock, and other conditions characterized by underlying MIF responses including, for instance, tumor growth and neovascularization.
Human MIF was first cloned in 1989 and its activity has been investigated in a number of studies. MIF was the first lymphokine to be discovered and was originally identified by its ability to prevent the migration of guinea pig macrophages in vitro (Bloom and Bennett, Science 153:80-82, 1966; David, Proc. Natl. Acad. Sci. USA 56:72-77, 1966). Given this activity, the role of MIF activity in inflammation and the immune system was investigated, however the precise role of MIF in either local or systemic inflammatory responses remained largely undefined in the course of this early work. Likewise the role of MIF in other physiological and pathophysiological is still being defined.
MIF was reported to be associated with delayed-type hypersensitivity reactions (Bloom and Bennett, 1966, supra; David, 1966, supra), to be produced by lectin-activated T-cells (Weiser et al., J. Immunol. 126:1958-1962, 1981), and to enhance macrophage adherence, phagocytosis and tumoricidal activity (Nathan et al., J. Exp. Med. 137:275-288, 1973; Nathan et al., J. Exp. Med. 133:1356-1376, 1971; Churchill et al., J. Immunol. 115:781-785, 1975). Unfortunately, many of these early studies used mixed culture supernatants that were shown later to contain other cytokines, such as IFN-xcex3 and IL-4, that also have macrophage migration inhibitory activity (McInnes and Rennick, J. Exp. Med. 167:598-611, 1988; Thurman et al., J. Immunol. 134:305-309, 1985).
Recombinant human MIF was originally cloned from a human T cell library (Weiser et al., Proc. Natl. Acad. Sci. USA 86: 7522-7526, 1989), and was shown to activate blood-derived macrophages to kill intracellular parasites and tumor cells in vitro, to stimulate IL-1xcex2 and TNFxcex1 expression, and to induce nitric oxide synthesis (Weiser et al., J. Immunol. 147:2006-2011, 1991; Pozzi et al., Cellular Immunol. 145:372-379, 1992; Weiser et al., Proc. Natl. Acad. Sci. USA 89:8049-8052, 1992; Cunha et al., J. Immunol. 150:1908-1912, 1993). While the conclusions available from several of these early reports are confounded by the presence of a bioactive mitogenic contaminant in the recombinant MIF preparations used, the potent pro-inflammatory activities of MIF have been confirmed in other studies that do not suffer from this complicating factor (reviewed in Bucala, The FASEB Journal 10:1607-1613, 1996). More recent MIF studies have capitalized on the production of recombinant MIF in purified form as well as the development of MIF-specific polyclonal and monoclonal antibodies to establish the biological role of MIF in a variety of normal homeostatic and pathophysiological settings (reviewed, for instance, in Rice et al., Annual Reports in Medicinal Chemistry 33:243-252, 1998). Among the most important insights of these later reports following the xe2x80x9cre-discoveryxe2x80x9d of MIF has been the recognition that MIF not only is a cytokine product of the immune system, but also is a hormone-like product of the endocrine system, particularly the pituitary gland. Moreover, this recent work has underscored the potent activity of MIF as a counter-regulator of the anti-inflammatory effects of the glucocorticoids (both those endogenously released and those therapeutically administered), with the effect that the normal activities of glucocorticoids to limit and suppress the severity of inflammatory responses are inhibited by MIF, such that the endogenous MIF response is seen as a cause or an exacerbative factor in a variety of inflammatory diseases and conditions (reviewed in Donnelly and Bucala, Molecular Medicine Today 3:502-507, 1997). MIF has also been linked to tumor growth and neovascularization (angiogenesis), suggesting a further need for MIF antagonists in the area of oncology and cancer treatment (Chesney et al., Molecular Medicine 5:181-191, 1999).
This experimental work underscores the need for inhibitors of MIF, and MIF antagonists have been identified and shown to have a variety of therapeutic activities, including activity for multiple inflammatory diseases, cytokine-mediated toxicities, asthma, and autoimmune diseases (e.g., rheumatoid arthritis, graft versus host disease, insulin-dependent diabetes, and various forms of lupus). These MIF antagonist agents, however, have been xe2x80x9cbiologicalxe2x80x9d agents that are designed to bind MIF (e.g., antibody) and to prevent its expression (e.g., antisense oligonucleotide). Such biological agents, unfortunately, have certain limitations with regard to their clinical utility. Therefore, there is a need in the art to discover and develop small organic molecules that function as MIF antagonists and further posses the benefits of small organic molecule therapeutics versus larger, polymeric protein and nucleic acid-based-based therapeutic agents.
The present invention provides a compound of Formula I: 
wherein X is nitrogen or carbon;
wherein Y is O, C(R1)2, or S;
wherein Z is OH, R1, xe2x80x94CH2xe2x80x94N(R1)2, or SR1;
wherein R1 is independently H, straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, or if R1 is attached to carbon (but not if R1 is attached to N or S), straight or branched C1-C6 alkoxy;
wherein R2 is a single or multiple substitution independently H, OH, R1, N(R1)2, SR1 or a halogen;
wherein R3 is absent, H, R1, or a halogen;
wherein * and C mark potentially asymmetric carbon atoms and, in each instance of R, X, Y, Z, R1, and R3 where * or C or both are asymmetric, all diastereomers are included in Formula I;
wherein R is the side-chain of any naturally occurring alpha amino acid such that R together with X, Y and Z comprise, when Y is O and Z is OH, an aromatic, aliphatic or heterocyclic D or L alpha amino acid moiety linked as a Schiff base or a reduced Schiff base (if X is N) or as a carba analog thereof (if X is C) to an optionally substituted benzaldehyde moiety, and wherein if Y is other than O, or Z is other than OH, R together with X, Y and Z comprise a substituted amino acid moiety, an analog of an amino acid moiety or a protected amino acid moiety;
and pharmaceutically acceptable salts thereof.
Preferably, X is N, Y is O, and Z is OMe such that together with R they form a protected L aliphatic or aromatic amino acid moiety. Preferably, R2 is OH, and R3 is H. Even more preferably R2 is in a para position to comprise a para-hydroxybenzaldehyde moiety.
A preferred subset of these preferred compounds is described by Formula II, wherein R is H (compound 1); wherein R is xe2x80x94CH3 (compound 2 or compound 2a corresponding to L alanine and compound 2b corresponding to D alanine); wherein R is xe2x80x94CH(CH3)2 (compound 3); wherein R is xe2x80x94CH2CH(CH3)2 (compound 4); wherein R is xe2x80x94CH(CH3)CH2CH3 (compound 5); wherein R is xe2x80x94CH2CH2SCH3 (compound 6); and wherein R is xe2x80x94CH2OH (compound 7). Formula II:
Still more preferred, R is the side-chain of a naturally-occurring aromatic alpha amino acid, X is N, Y is O, and Z is OMe such that together with R they form a protected L aromatic amino acid moiety. Most preferably, R2 is OH, and R3 is H. Most preferably, R2 is in a para position to comprise a para-hydroxybenzaldehyde moiety product. Most preferably, R is xe2x80x94CH2-phenyl (compound 8), or R is xe2x80x94CH2-para-hydroxyphenyl (compound 9), or R is xe2x80x94CH2-indoyl (compound 10).
The invention further provides a pharmaceutical composition comprising a compound of Formula I, as a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluant.
The invention further provides a compound of formula I, or a pharmaceutically acceptable salt thereof, as a pharmaceutical composition comprising either of the aforesaid, for use in a medicine or for the manufacture of a medicament for the treatment or prevention of cancer or of inflammatory disorders including arthritis, proliferative vascular disease, ARDS (acute respiratory distress syndrome), cytokine-mediated toxicity, sepsis, septic shock, psoriasis, interleukin-2 toxicity, asthma and MIF-mediated conditions. The present invention further provides a method for treating or preventing cancer, arthritis, proliferative vascular disease, ARDS (acute respiratory distress syndrome), cytokine-mediated toxicity, sepsis, septic shock, psoriasis, interleukin-2 toxicity, asthma, MIF-mediated conditions, autoimmune disorders including rheumatoid arthritis, insulin-dependent diabetes, multiple sclerosis, graft versus host disease, lupus syndromes, or any condition characterized by local or systemic MIF release or synthesis.
In accordance with the activity of MIF to interfere with the anti-inflammatory effects of steroids (such as the anti-inflammatory glucocorticoids), the compounds of Formula I find further utility to enhance the activity and therapeutic benefits of both endogenously arising and exogenously administered steroidal anti-inflammatory agents. Such benefits may, in some cases, be most evident by a reduced need for steroid therapy (e.g., lower dose amount or frequency; less potent agent; reduced need for systemic administration) or by reduced side-effects associated with steroid administration. The benefits of administering an MIF antagonist agent (and specifically a compound of Formula I) may be realized as a monotherapy, using only the MIF antagonist agent of the present invention, or as a combination therapy with additional anti-inflammatory agents, including especially, but without limitation, an anti-inflammatory steroid. Such combination therapy may be achieved through administration of a single formulation or pharmaceutical composition that combines the MIF antagonist agent (particularly an agent of Formula I) with at least one other anti-inflammatory agent (which may be a steroidal or a non-steroidal anti-inflammatory agent), or through administration of separate formulations or pharmaceutical compositions in conjunction with each other (e.g., one composition comprising the MIF antagonist agent of Formula I, and at least one other composition comprising at least one steroidal or non-steroidal anti-inflammatory agent), or both.